The invention relates to a solid preparation for oral administration of gene-related drugs.
A variety of gene-related drugs have been developed as useful pharmaceuticals, though in the case of producing them as a solid preparation for oral administration, there are problems such as that worsened fluidity of mixed powder due to wettability of a gene-related drug and viscosity after its moisture absorption causing a compressing problem, in the case of increase of the mixed amount, production of tablets with good disintegration becomes difficult, and, in addition that it is very difficult to keep stability of a gene-related drug during a production process. Furthermore, even if a solid preparation for oral administration can be produced, a gene-related drug is easily decomposed in digestive tracts due to the unusually high instability in it, and so on, therefore, it has been generally considered difficult to develop a solid preparation appropriate for oral administration.
On the other hand, in the development of a general solid preparation for oral administration, recently various attempts have been made to make a drug which easily loses its due to decomposition in small intestines to be absorbed in large intestines in which the enzyme activity of protein decomposition is remarkably low by delivering it to the organ. Illustrative of such examples are oral preparations by the inventors (International application WO, 94/10983, A) mainly for drugs of protein or polypeptide nature having a high specificity toward lower digestive tracts such as large intestines. However, as to a gene-related drug, a solid preparation for oral administration which is practical and effective has not been developed yet owing to the above reasons.
Consequently, the problem of the invention is to solve problems in the prior art described above in a gene-related drug and to provide a solid preparation for oral administration which is practical and effective. More specifically, it is to provide a solid preparation for oral administration of a gene-related drug in which compressing preparation is easy, preparation processes are stable, and it is effectively absorbed in the digestive tracts.
The inventors made extensive researches to solve the above problems and found out that the decomposition activity for a gene-related drug, as for drugs of peptide nature is remarkably low in large intestines compared with small intestines, and as the result of continuing further research based on such evidence the inventors accomplished the invention.
Namely, the invention relates to a solid preparation with a coating around the core containing a gene-related drug for oral administration with releasability in lower digestive tracts in small intestines is applied.
The invention also relates to a solid preparation for oral administration in which the core is formed by compressing mixed powder of a gene-related drug and additives appropriately containing a binder, a saccharide, a disintegrator, an excipient or the like, and its outside is coated with an inner layer comprising a cationic copolymer and with an outer layer comprising an anionic copolymer.
Further, the invention comprises the following embodiments.
The above solid preparation for oral administration wherein the mixed ratio of a gene-related drug and a binder is 1:0.2-1:5 or the mixed ratio of a gene-related drug, a binder and an excipient is 1:0.2:0.01-1:5:1.
The above solid preparation for oral administration wherein the mixed ratio of a saccharide contained in the core containing a gene-related drug is in the range of 20-60 wt. %.
The above solid preparation for oral administration wherein a disintegrator contained in the core containing a gene-related drug is in the range of 2-15 wt. %.
The above solid preparation for oral administration, characterized in that a disintegrator is mixed in the ratio of 1:0.05-1:10 against the mixed amount of a gene-related drug and produced.
The above solid preparation for oral administration wherein an excipient contained in the core containing a gene-related drug is in the range of 0.1-15 wt. %.
The above solid preparation for oral administration wherein a gene-related drug contained in the core of the gene-related drug is in the range of 0.1-50 wt. %.
The above solid preparation for oral administration wherein a binder contained in the core containing a gene-related drug is in the range of 5-40 wt. %.
The above solid preparations for oral administration wherein the disintegrators are crospovidone, alpha starch, sodium carboxymethyl starch, carmellose, calcium carmellose, sodium carmellose, agar powder, sodium croscarmellose, crystalline cellulose, low substituted hydroxypropyl cellulose, starch, dextrin, hydroxyethylmethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, macrogol and mannitol.
The above solid preparations for oral administration wherein the saccharide are monosaccharides and disaccharides such as lactose, fructose, sucrose, glucose, xylitol, maltose, mannitol and sorbitol, or polysaccharides and derivatives thereof such as cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, ethyl cellulose, starch, dextrin, dextran, pectin and pullulan.
The above solid preparations for oral administration wherein the excipients are light anhydrous silicic acid, ethyl cellulose, carmelose, agar, magnesium aluminosilicate, calcium silicate, magnesium silicate, cyclodextrin, starch, synthetic aluminum silicate, synthetic hydrotalcite, titanium oxide, zinc oxide, magnesium oxide, alumina magnesium hydroxide, magnesium stearate, calcium stearate, aluminum silicate, talc, crystalline cellulose and lactose.
The above solid preparations for oral administration wherein the gene-related drugs are DNA, RNA and modified compounds thereof, and compounds thereof conjugated or bound to a carrier.
The above solid preparations for oral administration wherein the binders are crystalline cellulose, gumarabic, sodium alginate, ethyl cellulose, agar, carboxyvinyl polymer, carmelose, gelatin, low substituted hydroxypropyl cellulose, starch, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, pectin, polyvinylpyrrolidone, macrogol and methyl cellulose.
The above solid preparations for oral administration wherein the carriers comprise a cationic polymer, cationic lipid, virus vector and phage.
The above solid preparations for oral administration wherein the gene-related drugs comprise a nucleic acid, oligonucleotide, antisense, triple helix forming oligonucleotide (TFO), ribozyme, decoy, plasmid, cosmid, P1 phage, YAC (yeast artificial chromosome), chromosome, aptamer and phage.
Thus, the above problems were solved once for all by the solid preparations for oral administration of the invention.
In the invention, illustrative of available gene-related drugs are DNA, RNA and modified compounds thereof, and compounds thereof conjugated or bound to a carrier, nucleic acid, oligonucleotide, antisense, triple helix forming oligonucleotide (TFO), ribozyme, decoy and plasmid. Illustrative of the carriers used are cationic polymer, cationic lipid, virus vector and phage.
Specifically, in the case of aiming at the colitis therapy as a topical therapeutic use are illustrated suppressive type gene pharmaceuticals such as TNF-xcex1 (Tumor necrosis factor xcex1), ICAM-1 (Intercellular adhesion molecule-1), COX-2 (Cyclooxygenase-2), IL-1 (Interleukin-1), IL-6 (Interleukin-6) and IL-8 (Interleukin-8), or expression type gene pharmaceuticals such as IL-2 (Interleukin-2) and IL-10 (Interleukin-10). In the case of aiming at the colon cancer are illustrated suppressive type gene pharmaceuticals such as ICAM-1, COX-2 and TGF-xcex2 (Transforming growth factor xcex2), or expression type gene pharmaceuticals such as INF-xcex3 (Interferon-xcex3), TNF-xcex1, APC (Adenomatous Polyposis Coli), p53, MCC (Mutated in Colorectal Carcinoma) and DCC (deleted in colorectal carcinomas). Further, in the case of aiming at the systemic diseases are illustrated suppressive type gene pharmaceuticals such as TNF-xcex1, ICAM-1, COX-2, IL-1, IL-6, HIV (human immunodeficiency virus), bile acid transporter and each transporter of the small intestine, or expression type gene pharmaceuticals such as INF-xcex3, TNF-xcex1, G-CSF (Granulocyte colony-stimulating factor), GM-CSF (Granulocyte macrophage colony-stimulating factor), glucose transporter, LHRH (Luteinizing hormone-releasing hormone) and calcitonin.
Also, in the invention, as to the above additives, an appropriate material and an appropriate mixed amount are selected by considering the fluidity of mixed powder, the disintegration of tablets, and the stability at the time of production.
In the following, the embodiments of the preparations are explained according to the method of production, the invention however, is not limited in any way by these.
First, the gene-related drug and the binder, or the gene-related drug, the binder and the excipient are mixed and ground using an appropriate micro-smasher such as an agate mortar, jet mill, pin mill or ball mill.
Here, illustrative of the available binders are crystalline cellulose, gum arabic, sodium alginate, ethyl cellulose, agar, carboxyvinyl polymer, carmelose, gelatin, low substituted hydroxypropyl cellulose (trade name; L-HPC, Shinnetsu Kagaku Kogyo Co., Ltd.), starch, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, pectin, polyvinylpyrrolidone, macrogol and methyl cellulose. Preferably crystalline cellulose is used.
Further, illustrative of the excipients are light anhydrous silicic acid, ethyl cellulose, carmellose, agar, magnesium silicate aluminate, calcium silicate, magnesium silicate, cyclodextrin, starch, synthetic aluminum silicate, synthetic hydrotalcite, titanium oxide, zinc oxide, magnesium oxide, alumina magnesium hydroxide (aluminum magnesium hydroxide), magnesium stearate, calcium stearate, aluminum silicate, talc, crystalline cellulose and lactose. Preferably light anhydrous silicic acid is used.
The mixed ratio of the binder contained in the core containing the gene-related drug is 5-40 wt. %., preferably 10-25 wt. %., likewise the mixed ratio of the excipient is 0.1-15 wt. %., preferably 1-5 wt. %., furthermore likewise the mixed ratio of the gene-related drug is 0.1-50 wt. %., preferably 5-30 wt. %.
On the other hand, the mixed ratio of the gene-related drug and the binder is in a preferable range for the fluidity of the mixed powder, the disintegration of tablets and the compressibility, specifically 1:0.2-1:5, preferably: 1:0.5-1:2. From the same standpoint, the mixed ratio of the gene-related drug, the binder and the excipient is 1:0.2:0.01-1:5:1, preferably 1:0.5:0.02-1:2:0,05.
Subsequently, the saccharide and the disintegrator is added to the obtained mix-ground product and mixed. Magnesium stearate is added to the mixture, and compressed with an appropriate tablet machine.
Here, illustrative of the saccharide are monosaccharides and disaccharides such as lactose, fructose, sucrose, glucose, xylitol, maltose, mannitol and sorbitol, or polysaccharides and derivatives thereof such as cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, ethyl cellulose, starch, dextrin, dextran, pectin and pullulan. Preferably lactose is used.
Here, illustrative of the disintegrators are crospovidone, alpha starch, sodium carboxymethyl starch, carmellose, calcium carmellose, sodium carmellose, agar powder, sodium croscarmellose, crystalline cellulose, low substituted hydroxypropyl cellulose (trade name; L-HPC, Shinnetsu Kagaku Kogyo Co., Ltd.), starch, dextrin, hydroxyethylmethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, macrogol and mannitol. Preferably crospovidone is used.
The mixed ratio of the excipient contained in the core containing the gene-related drug is 2-25 wt. %., preferably 5-15 wt. %., likewise the mixed ratio of the sugar is 20-60 wt. %., preferably 30-50 wt. %. The mixed ratio of the disintegrator against the mixed amount of the gene-related drug is in the range preferable for having a suitable disintegration in order to be delivered to the target site in the digestive tracts and for the compressibility, specifically in the ratio of 1:0.05-1:10, preferably 1:0.1-1:5. The mixed ratio of crospovidone as the disintegrator is in the range of 2.5-20 wt. %., preferably 5-15 wt. %.
Subsequently, the surface of the obtained uncoated tablet (core) is coated with the cationic copolymer and further with the anionic copolymer. As to the coating, coating solution is continuously applied by spraying under the condition that said core is kept at 30-50xc2x0 C. The weight increase due to the cationic copolymer and the anionic copolymer is 5-15 wt. % based on the weight of the uncoated tablet, preferably 6-8 wt. %.
The cationic copolymer used as the inner layer has properties to be soluble or swelling at pH of 6.0 or below. Famous polymers include aminoalkyl methacrylate copolymer, a general name [copolymer comprising methyl methacrylate, butyl methacrylate and dimethyaminomethyl methacrylate, trade name: Eudragit E, manufactured by Rxc3x6hm Co., Ltd.] or polyvinyl acetal diethylaminoacetate (trade name: AEA, manufactured by Sankyo Co., Ltd.). This polymer layer (inner layer) is formed by the use of membrane having the thickness of 10-300 xcexcm and 1-40 wt. % of said solid drug weight, and regulated so as to release the active substance from said solid drug quickly when the pH condition of 6.0 or below continues. As for this inner layer, a suitable plastisizer is preferably used to obtain smooth coating membrane. The plastisizer includes triacetin, citric acid ester and polyethylene glycol. Also, the binding inhibitor includes talc, titanium oxide, calcium phosphate, hydrophobic light anhydrous silicic acid, etc.
The anionic copolymer used as the outer layer has a property to be easily soluble at pH of 5.5 or above. Famous polymers include methacrylic acid copolymer L, a general name, (copolymer comprising methacrylic acid and methyl methacrylate, tradename: Eudragit L100, manufactured by Rxc3x6hm Co., Ltd.), methacrylic acid copolymer S (copolymer comprising methacrylic acid and methyl methacrylate, trade name: Eudragit S, manufactured by Rxc3x6hm Co., Ltd.), hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, etc. Said polymer is used in 1-40 wt. % of said solid drug.
According to the preparations, the gene-related drug can be delivered to the lower digestive tracts which can absorb it maintaining its activity stable, in particular to large intestines specifically, and the preparations disintegrate quickly at the same time of their delivery, therefore, the gene-related drug, which is a pharmacologically active substance, is released without loss of its activity. Further, at the time of production, the fluidity of powder is not destroyed to make stable compressing of tablets possible, and furthermore the stability of the gene-related drug can sufficiently be guaranteed in the time of production.